769022

review-article2018
PEV0010.1177/2284026518769022Journal of Endometriosis and Pelvic Pain DisordersSaguyod et al.

JEPPD Journal of
Endometriosis and
Pelvic Pain
Review Disorders

Journal of Endometriosis and

Diet and endometriosis-revisiting the

Pelvic Pain Disorders
1­–8
© The Author(s) 2018
linkages to inflammation Reprints and permissions:
sagepub.co.uk/journalsPermissions.nav
https://doi.org/10.1177/2284026518769022
DOI: 10.1177/2284026518769022
journals.sagepub.com/home/pev

Sofia Jade U Saguyod1, Angela S Kelley2, Michael C Velarde1

and Rosalia CM Simmen3,4

Abstract
Endometriosis is a chronic inflammatory condition that may cause pelvic pain, dysmenorrhea, and/or infertility in women
of reproductive age. While treatments may include medical or surgical management, the majority of therapeutic options
are non-curative, and women may experience longstanding pain and/or disability. In general, chronic diseases are
believed to result from modifiable risk factors, including diet. In this review, we discuss recent data on evidence-based
associations between diet and endometriosis and the mechanistic points of action of constituent dietary factors with
emphasis on inflammatory events that may contribute to the promotion or inhibition of the disease. Understanding the
convergence of diet and endometriosis may lead to the development of clinical strategies to improve the quality of life
for symptomatic women.

Keywords
Diet, endometriosis, inflammation, cytokines

Date received: 19 December 2017; accepted: 15 March 2018

Introduction
Endometriosis, a condition histologically characterized by
the presence of viable endometrial glands and stroma in
extrauterine locations such as in the peritoneum, ovary,
and bowel, is a chronic disease that causes pelvic pain,
dysmenorrhea, and/or infertility in up to 10% of women of
reproductive age.1,2 Because the condition is latent at the
very early stages and may remain undiagnosed for many
years after onset of symptoms, it can significantly progress
by the time of clinical diagnosis, with limited treatment
options in advanced stages.3 Surgical removal of lesions
generally provides only temporary relief since the condi-
tion has a high incidence of recurrence.3 In some cases,
use, Western diet, and physical inactivity, are considered
mostly preventable.6 According to the Global Burden of
Disease study,7 diet is a leading risk factor for early death
worldwide, second only to smoking. Indeed, approxi-
mately 60% of all cancer types may be attributed to meta-
bolic syndrome and its accompanying components of
obesity and Type 2 diabetes, which are due largely to over-
nutrition.8 In the United States, obesity has reached almost
1Institute of Biology, University of the Philippines Diliman, Quezon
City, Philippines
2Department of Obstetrics and Gynecology, University of Michigan

surgery may compromise ovarian function.4 Moreover, a Health System, Ann Arbor, MI, USA
significant fraction of patients do not respond or develop 3Department of Physiology and Biophysics, University of Arkansas for

resistance to hormonal treatments.5 Thus, identifying pre-
ventative and alternative therapeutic strategies for man-
agement of endometriosis continues to be of high priority.
Chronic diseases have emerged as a considerable global
health burden, in lieu of infectious diseases that have rap-
idly declined in the last 20 years. Risk factors for the
majority of chronic diseases, including smoking, alcohol
Medical Sciences, Little Rock, AR, USA
4Winthrop P. Rockefeller Cancer Institute, University of Arkansas for
Medical Sciences, Little Rock, AR, USA
Corresponding author:
Rosalia CM Simmen, Department of Physiology and Biophysics,
University of Arkansas for Medical Sciences, 4301 West Markham
Street, Little Rock, AR 72205, USA.
Email: simmenrosalia@uams.edu
2 Journal of Endometriosis and Pelvic Pain Disorders 00(0)
epidemic proportions with nearly 40% of adults and 19%
of children categorized as metabolically compromised.
Given the latter and the increasing incidence of obesity
globally, it is reasonable to predict that in the absence of
effective interventions, the incidence of chronic diseases
will only escalate with accompanying personal and socio-
economic consequences.9
In recent years, endometriosis has been increasingly
linked to ovarian, endometrial, and breast cancers.10–12 A
significant proportion of these steroid hormone-dependent
cancers are tied to metabolic dysfunctions. A known trig-
ger for metabolic syndrome is inflammation initiated by
over-production and secretion of local- or systemic-acting
pro-inflammatory cytokines. Given that women with
endometriosis demonstrate a state of chronic inflamma-
tion,13 treatments that reduce inflammation may mitigate
the risk or severity of endometriosis. In this review, we
discuss recent data on evidence-based associations
between diet and endometriosis and the mechanistic points
of action of constituent dietary factors that may contribute
to promotion or inhibition of the disease.
Diet and endometriosis—the linkages
Population studies to date support an inverse associa-
tion of endometriosis with body mass index (BMI).14
Interestingly, endometriosis is associated with lean
body size during childhood, adolescence, and adult-
hood.15 This relationship between BMI and endometrio-
sis appears counter-intuitive, but can be explained to
some extent by the fact that obese women may suffer
from anovulation, fewer menstrual cycles and hence,
decreased menstrual tissue reflux, the latter being the
most accepted etiology for endometriosis.16 However,
there are sporadic reports on a positive association
between increasing BMI and advancing-stage endome-
triosis17 and between prepubertal obesity and endome-
triosis recurrence risk.18 Given these conflicting
findings, the question on whether obesity results in
endometriosis or whether the presence of endometriosis
leads to obesity remains unresolved.
Metabolic dysfunction and obesity usually co-exist but
disrupted metabolic status can also arise independent of
body weight. Indeed, metabolic syndrome rather than BMI
better predicts cardiovascular risk in women and inflam-
matory activity is more closely associated with metabolic
status than body weight.19 In a study of women with and
without endometriosis, differing plasma metabolite pro-
files were associated with and predictive of disease occur-
rence.20 A recent study addressed the causal relationship
involving BMI, metabolic status, and endometriosis in a
mouse model of the disease.21 Mice with experimentally
induced endometriosis were found to display lower body
weights than sham controls after 21 weeks of ad libitum
feeding, leading to the conclusion that endometriosis is
causal to loss of body weight and body fat. The lower BMI
consequent to endometriosis was attributed to disruption
of hepatic liver metabolism, providing a mechanistic link
to the poorly understood metabolic component of endome-
triosis. While these findings offer support for the negative
correlation between BMI and endometriosis, they chal-
lenge the long-held view that lower BMI is a risk factor for
endometriosis and a predictive factor for severe endome-
triosis. Further assessment of the systemic and local
(lesion, peritoneal) inflammatory phenotypes in these mice
will provide important insight on the link between meta-
bolic perturbations and inflammation in women with
endometriosis.
Our own study implicated a causal link between diet
and endometriosis in an immune-competent mouse model
of the disease.22 We found that diets which differed only
in fat content (high-fat diet, HFD: 45% fat kcal vs control
diet, CD: 17% fat kcal) and provided ad libitum to recipi-
ent mice beginning at weaning (5 weeks prior to intra-
peritoneal lesion administration) and for an additional
4 weeks after endometrial tissue i.p. administration, elic-
ited significant differences in lesion number (HFD > CD),
lesion inflammatory and redox status (HFD > CD), and
systemic/peritoneal fluid redox levels (HFD > CD). No
differences in body weights and in serum levels of estro-
gen, progesterone, and insulin were noted between the
two groups. These results indicate that diets promoting
systemic inflammation and oxidative stress can enhance
endometriosis progression. Furthermore, they lend sup-
port to the notion that adiposity is not a major contributor
to endometriosis risk.
Table 1 summarizes recent studies (2000 to present)
that have experimentally evaluated dietary effects on
endometriosis progression using animal models of endo-
metriosis and women with diagnosed endometriosis.
Manuscripts reporting prospective data wherein diets
were assessed via food frequency questionnaires and
hence, maybe subject to recall bias, are not included in
this review. Several important points are worth-noting
from these collective studies. First, dietary factors with
known anti-inflammatory effects can mitigate disease
progression, assessed as lesion size in mouse models and/
or decreased risk for advanced endometriosis stage and/or
reduction in pain symptoms in afflicted patients. The vari-
ous dietary factors evaluated (e.g. green tea, resveratrol,
fish oil, soy isoflavones) have shown health benefits in
many previous experimental animal and human studies,
and thus, their ability to alleviate endometriosis is not
entirely surprising. Second, women with endometriosis
(and their lesion stromal cells) and mouse models of the
condition respond similarly to dietary factors with anti-
inflammatory effects, consistent with chronic inflamma-
tion as an underlying driver in endometriosis establishment
and progression. Third, polyunsaturated fatty acids, fish
oils, vitamins, and flavonoids as candidate molecules in
Saguyod et al. 3

Table 1.  Dietary factors and endometriosis risk.

Dietary factors Sources Model Biological outcome Molecular targets References

Isoflavones Fruits, Women with ↓ Severity ↑ Autophagy Jamillian and Asemi26
(genistein, vegetables, endometriosis ↓ Proliferation ↓ NF-κB activity Yu et al.27
daidzein, other edible Endometrial stromal ↓ Vascular formation ↓ TGF-β, TNF-α, and Danciu et al.28
puerarin) plants cells (women with ↓ Invasive ability IL-6 Tsuchiya et al.29
endometriosis) ↓ Lesion volume ↓ Oxidative stress Wang et al.30
Mice ↓ MAPK signaling Cheng et al.31
Rats pathway Ji et al.32
↓ MMP9, MMP1 Yavuz et al.33
↓ P450 aromatase Chen et al.34
expression
Stillbenoid Red grapes, Endometrial stromal ↓ Severity ↑ TRAIL-induced Taguchi et al.35,36
(resveratrol) peanuts, cells (women with ↓ Lesion size and apoptosis Ergenoğlu et al.37
pistachio, other endometriosis) number ↓ Survivin Bruner-Tran et al.38
berries Mice ↓ TNF-α Ohtsu et al.39
↓ IL-6
↓ Peritoneal fluid and
lesion VEGF
↓ Peritoneal and
plasma MCP-1
↓ NF-κB activity
↓ STAT-3 activation
↓ iNOS, COX2, and
prostaglandin F2α
↑ Sirtuin
↑ Autophagy and
AMPK-dependent
pathways
Vitamin D Fatty fish Endometrial stromal ↓ Severity ↓ IL-8 Miyashita et al.40
Dairy products cells (women with ↓ Lesion size ↓MMP2/MMP9 Abbas et al.41
endometriosis) ↓ Lesion weight ↓ Prostaglandin activity Mariani et al.42
Rats ↓ NF-κB activity
Mice ↓ IL-6
↓ Macrophage
recruitment
Omega-3 fatty Fatty fish, Rats ↓ Lesion numbers ↓ Peritoneal IL-6 Akyol et al.43
acids walnuts, edible Mice ↓ TNF-α Attaman et al.44
seeds, soybeans ↓ VEGF Tomio et al.45
↓ Lesion IL-6
↓ Lesion VEGF
Epigallocatechin Green tea Mice ↓ Lesion size ↓ VEGF-B/C Xu et al.46
gallate ↓ Angiogenesis expression Xu et al.47
parameters ↓ VEGF/VEGF
receptor signaling

NF-κB: nuclear factor-κB; TGF-β: transforming growth factor-β; TNF-α: tumor necrosis factor-α; IL-6: interleukin-6; MMP: matrix metalloprotein-
ase; VEGF: vascular endothelial growth factor; MAPK: mitogen-activated protein kinase; TRAIL: tumor necrosis factor-related apoptosis-inducing
ligand; STAT-3: signal transducer and activator of transcription-3; iNOS: inducible nitric oxide synthase; COX2: cyclooxygenase 2; AMPK: 5’ adenos-
ine monophosphate-activated protein kinase.

the management of endometriosis pain and in reducing
lesion size are in keeping with previous reports from die-
tary recall questionnaires suggesting a negative associa-
tion between consumption of fish oils, green vegetables,
fruits and dairy products, and endometriosis risk.23–25
In a recent study, gluten-free diet showed a significant
positive effect in reducing pain symptoms in endometrio-
sis patients.48 The retrospective study involving 150
women in each of two groups (group 1 = gluten-free
diet + dienogest; group 2 = dienogest alone) is a single
report that requires additional follow-up investigation.
However, gluten-free diet is prescribed for patients with
celiac disease caused by an overactive cytokine net-
work.49,50 Moreover, women with celiac disease demon-
strated increased risk for endometriosis51 and infertility.52
Thus, this dietary regimen may be equally useful in tem-
pering the heightened inflammatory status associated with
endometriosis.
4 Journal of Endometriosis and Pelvic Pain Disorders 00(0)
Figure 1.  Schematic diagram of inflammation-mediated
events in endometriosis and potential intervention points for
diet/dietary factors. Inflammation can result in endometriosis
lesion establishment through multiple pathways, which may be
targeted by dietary factors (described in text).
PUFA: polyunsaturated fatty acids; EGCG: epigallocatechin gallate; NF-
κB: nuclear factor-κB; KLF9: Krüppel-like factor 9; PGR: progesterone
receptor; ESR2: estrogen receptor-β; ˧: inhibitory effect; ↑: stimulatory
effect; ?: unknown.
Molecular targets of dietary
components in endometriosis
The link between endometriosis and systemic/local
immune dysfunctions, while well-established,13,53
remains a “chicken or egg” dilemma. In effect, it is not
known whether endometriosis predisposes to an inflam-
matory state or whether chronic inflammation leads to
the development of endometriosis. Nevertheless, the
inflammatory environment caused by endometriosis is
considered to contribute to infertility due to effects of
pro-inflammatory cytokines on endometrial receptivity
and embryo implantation54,55 and to other pregnancy
complications in women with the disease.56 In a recent
review, Alderman et al.57 described how systemic effects
associated with endometriosis may underlie its co-mor-
bidities including cancers, cardiovascular and autoim-
mune diseases, and pain. Several signaling molecules
including cytokines, chemokines, and micro-RNAs, and
the recruitment of bone marrow-derived stem cells into
endometriotic lesions were discussed as contributory to
systemic pathogenesis in endometriosis. Readers are
referred to this review for more details.57
Since inflammation is potentially at the top of the
regulatory loop leading to endometriosis, maintaining a
systemic non-inflammatory state or targeting low-level
inflammation may conceivably alleviate endometriosis
development and/or recurrence. Studies from our own
group in conjunction with findings from other
laboratories suggest a plausible mechanism by which
inflammation may initiate the process of endometriosis
at the level of the endometrium (Figure 1). This model
invokes the loss of expression of certain regulatory mol-
ecules (e.g. Krüppel-like factor 9 (KLF9), progesterone
receptor) and the over-expression of others (estrogen
receptor-β, interleukin-6 (IL-6), Notch-1 activation)
leading to compromised uterine glands and stroma with
unique molecular defects that foster their residence in
ectopic sites.58 The loss of KLF9 promoted lesion estab-
lishment in a mouse model of endometriosis,59 consist-
ent with the lower abundance of KLF9 transcripts found
in eutopic endometria of women with endometriosis
relative to endometria of women without disease.60
Resistance to progestin is a well-established feature of
eutopic endometria and ectopic lesions of women with
endometriosis due in part, to loss of progesterone recep-
tor expression.61 The over-expression of estrogen
receptor-β leads to inflammation in endometriosis,62 and
interestingly, lesions lacking KLF9 from experimentally
induced endometriosis in mice were associated with
increased levels of this estrogen receptor isoform.59
Additionally, Notch-1 signaling activation promotes63
and is promoted64 by inflammation, is linked to endome-
triosis in a mouse model,59 and is shown to downregulate
progesterone receptor expression via increased promoter
methylation in uterine endometrial cells.65 Finally, the
pro-inflammatory molecule IL-6, an inhibitor of proges-
terone receptor expression,66 is up-regulated in endome-
triotic lesions,59,67 whereas progesterone inhibits
inflammatory response pathways in uterine endometri-
otic stromal cells.68 While there are gaps in this model
given the current unknowns and the multi-factorial and
polygenic nature of endometriosis, it is reasonable to
predict that diets and dietary factors that can signifi-
cantly impact inflammation-initiated events may influ-
ence endometriosis progression and recurrence.
The current literature highlights an abundance of anti-
inflammatory foods recommended by nutrition experts,
which consist of fruits and vegetables, whole grains, plant-
based foods (beans, nuts), fatty fish, and spices. The
molecular targets of the various dietary constituents pre-
sent in these anti-inflammatory foods that may be useful to
ameliorate endometriosis are presented in Table 1.
Phytoestrogens present in many vegetables, fruits, and
other edible plants include isoflavones, lignans, and stilbe-
noids. Isoflavones can influence inflammation through
multiple mechanisms namely promotion of autophagy,
down-regulation of transcription factor nuclear factor-κB
(NF-κB) activity, reduction of inflammatory cytokine pro-
duction (e.g. transforming growth factor-β (TGF-β), tumor
necrosis factor-α (TNF-α), IL-6), and inhibition of oxida-
tive stress.26–28 In line with the anti-inflammatory effects
of isoflavones, women with endometriosis consuming iso-
flavones (measured by urinary levels of genistein and
Saguyod et al. 5
daidzein) showed decreased risk of advanced endometrio-
sis (Stages III and IV)29 and incorporation of soy isofla-
vone genistein in diets of mice with endometriotic implants
resulted in regression of ectopic lesions relative to diets
without genistein.33
Another isoflavone found in arrowroots endemic to
Japan and China is puerarin. Puerarin demonstrates inhibi-
tory effects on estradiol-17β-induced proliferation, vascu-
larization, and invasive ability of stromal cells isolated
from women with endometriosis. Multiple mechanisms
through which it is considered to exert its actions include
the targeting of matrix metalloproteinase 9 (MMP9) and
tissue inhibitor of metalloproteinase-1 expression, inhibit-
ing the recruitment of nuclear receptor co-regulators to the
estrogen receptor-α in promoter/regulatory regions of tar-
get genes, and suppressing the mitogen-activated protein
kinase (MAPK) signaling pathway.30–32 In a rat model of
endometriosis, orally administered puerarin reduced lesion
estrogen production by inhibiting local aromatase expres-
sion, resulting in reduced lesion volume.34 These collec-
tive data suggest the potential for puerarin as a therapeutic
agent for disease management.
Resveratrol, a stillbenoid, is a polyphenol found in foods
such as red grapes, peanuts, pistachio, blueberry, and vari-
ous other berries. This compound was found to decrease
ectopic lesion size in a mouse model of endometriosis con-
current with reductions in peritoneal fluid vascular endothe-
lial growth factor (VEGF) and peritoneal and plasma
monocyte chemoattractant protein-1 levels, and in lesion
VEGF expression.37 In a nude mouse model implanted with
human endometriotic tissues, systemic administration of
resveratrol decreased lesion numbers (by 60%) and volume
(by 80%); this was partly attributed to the reduction of the
ability of endometriotic stromal cells to invade matrix in
vitro with resveratrol treatment.38 In endometriotic stromal
cells derived from women with endometriosis, resveratrol
inhibited survivin expression, enhanced tumor necrosis
factor-related apoptosis-inducing ligand (TRAIL)-induced
apoptosis,36 and dose-dependently suppressed TNF-α-
induced release of the pro-inflammatory cytokine IL-6.35
Other potential mechanisms by which resveratrol may
inhibit lesion establishment via its anti-inflammatory
effects, based largely on its actions in other target systems,
include inhibition of NF-κB activity, signal transducer and
activator of transcription-3 (STAT-3) activation, and pro-
duction of inducible nitric oxide synthase (iNOS), cycloox-
ygenase-2 (COX2), and prostaglandin F2α and conversely,
promotion of autophagy, 5’ adenosine monophosphate-
activated protein kinase (AMPK)-dependent pathways, and
sirtuin expression.39
Vitamin D is a fat-soluble sub-class of steroids with
multiple endocrine effects. While vitamin D is naturally
found at high levels in foods such as fatty fish (salmon,
tuna, mackerel) and in smaller amounts in others (cheese,
egg, liver), many foods consumed by the general
population (milk, yogurt, orange juice) are fortified with
vitamin D. The involvement of vitamin D in endometriosis
has been studied in women and in experimental animal
models. In a double-blind clinical trial involving women
with diagnosed endometriosis, Vitamin D supplementation
had no effect in reducing dysmenorrhea and/or pelvic pain,
relative to those without supplementation.69 However, in
an observational study involving women with ovarian
endometriosis, those with lower serum levels of vitamin D
(considered hypovitaminosis D) were more prone to have
endometriosis than women with normal serum vitamin D
levels. Interestingly, a linear correlation between serum
1,25(OH)-D3 levels and diameter of ovarian endometrio-
mas was reported.70 Women with severe endometriosis
were also found to have significantly lower serum
1,25(OH)-D3 levels than non-diseased women and women
with mild endometriosis.40 Furthermore, in endometrial
stromal cells cultured from ovarian endometriomas, addi-
tion of 1,25(OH)-D3 elicited an anti-inflammatory
response, manifested as reductions in IL-8 and MMP2/
MMP9 expression, prostaglandin activity, and NF-κB acti-
vation, relative to non-treated cells.40 In animal models of
endometriosis, vitamin D3 significantly reduced endome-
triotic lesion sizes (by 48%) in rats.41 In mice, injection of
elocalcitol, a vitamin D agonist decreased lesion weight up
to 70%, and this was associated with reduced peritoneal
inflammation, inhibition of macrophage recruitment and
diminished cytokine IL-6 secretion.42
Epigallocatechin gallate (EGCG) from green tea has
powerful anti-angiogenic and anti-oxidant properties and
predictably, has been linked to inhibition of endometriosis-
like lesion formation in mouse models. Transplanted
eutopic endometria isolated from patients with endome-
triosis generated smaller lesions with significantly reduced
microvessel size and density and lower VEGF-B/C expres-
sion in nude mice ip injected with EGCG than with vehicle
alone.46 The reduced macrovascular network in lesions
was shown to be mediated by EGCG inhibition of VEGF/
VEGF receptor signaling occurring through interferon-γ,
MMP9, and chemokine ligand 3 pathways.47 Interestingly,
vitamin E (a non-angiogenic anti-oxidant) did not mimic
EGCG-elicited effects on lesions, suggesting angiogenesis
as a major target of EGCG actions.46
Of high relevance to endometriosis is consumption of a
HFD, given the latter’s known effects in promoting meta-
bolic dysfunction. Studies on the consequences of fat con-
sumption (e.g. saturated fat in red meat) on endometriosis
progression in women have not yielded a clear consensus of
an association.23,25 By contrast, a negative association
between HFD and endometriosis22 was established in a rel-
evant mouse model of the condition. Nevertheless, the ben-
efits of certain dietary fats (e.g. omega-3 polyunsaturated
fatty acid (omega-3 PUFA)) on reducing endometriosis risk
in women, based on prospective data,23 were consistent with
those obtained from animal studies. In particular, intake of
6 Journal of Endometriosis and Pelvic Pain Disorders 00(0)
3-PUFA in a rat model of experimentally induced endome-
triosis caused significant regression of endometriotic
implants, concomitant with decreased peritoneal levels of
IL-6, TNF-α, and VEGF.43 Moreover, transgenic Fat-1 mice
which express high levels of endogenous 3-PUFA also dis-
played smaller endometriosis-like lesions and lower lesion
IL-6 and VEGF levels when used as an endometriosis
model, relative to wild-type mice.44 Furthermore, using the
same Fat-1 endometriosis model, feeding with eicosapen-
taenoic acid (EPA), an omega-3-fatty acid found in cold-
water fatty fish such as salmon and in fish oil supplements,
caused the suppression of endometriotic lesion formation in
the peritoneum, which was attributed to lower IL-6 levels
mediated by the 12/15-lysyl oxidase-pathway products of
EPA.45 In women, the relevance of EPA to endometriosis
risk was evaluated in a cross-sectional study wherein women
undergoing in vitro fertilization were measured for specific
serum and total PUFAs and surveyed for their history of
endometriosis. Result indicated an inverse correlation
between serum EPA levels and endometriosis risk, that is,
women with high serum EPA levels had 82% lower risk of
endometriosis compared to women with low EPA levels.71
Conclusion and future directions
Diet and nutrition have come of age to be at the forefront
in the fight against endometriosis, based on recent evi-
dence-supported studies describing the ability of foods
with anti-inflammatory actions to mitigate endometriosis
progression in animal models and patients alike.
Nevertheless, there are some caveats to consider with the
very promising data generated thus far. First, studies con-
ducted in animal models predominantly utilized purified
dietary factors, and the doses and routes of administration
(intraperitoneal, oral gavage) do not recapitulate standard
consumption by the general population. Second, in studies
using immune-deficient mouse models, the lack of normal
systemic anti-defense mechanisms may be confounding to
the actual elicited benefits; hence, there is a need to re-
examine these reported effects in validated immune-com-
petent experimental animal models of endometriosis.22,62
Third, the period and duration of dietary exposure/con-
sumption may need to be carefully considered in the design
of clinical interventions and in studies using animal mod-
els, given that systemic environments significantly differ
in reproductively aged women (e.g. young vs middle-age
adults; obese vs normal weight) and in those with varying
severity of the disease. Fourth, rodent models and humans
can significantly vary with respect to bioavailability of
dietary factors and tissue uptake. Finally, while the value
of epidemiological studies cannot be underestimated in
developing health policies and system research to achieve
health goals, the limitations of recall-based studies must be
taken into account when designing personalized therapeu-
tic interventions for afflicted patients.
More effective interventions are required to address
endometriosis. Understanding the convergence of diet and
endometriosis may generate integrated strategies in clini-
cal practices to improve the quality of life for sympto-
matic women. Dietary modification as a complementary
approach and a short-term recourse to reduce the effects
of inflammation associated with endometriosis is feasible,
practical and can be monitored under physician supervi-
sion. Nevertheless, due in part to the complex nature of
the condition and the lack of reliable markers to detect
disease initiation, scientific-based data are currently defi-
cient to support the ability of anti-inflammatory foods and
food components to prevent endometriosis. Thus, a long-
term goal for endometriosis research is to achieve a clear
appreciation of key mechanisms that underlie disease
pathology that can be targeted by dietary factors to man-
age not only disease progression and recurrence but for
disease prevention.
Declaration of conflicting interests
The author(s) declared no potential conflicts of interest with
respect to the research, authorship, and/or publication of this
article.
Funding
The author(s) disclosed receipt of the following financial support
for the research, authorship, and/or publication of this article:
This work was supported in part, by the University of Arkansas
for Medical Sciences Translational Research Institute (RCMS)
and the University of the Philippines Office of the Vice President
for Academic Affairs—Emerging Interdisciplinary Research
(OVPAA-EIDR-C08-006) (MCV, RCMS).
References
1. Giudice LC and Kao LC. Endometriosis. Lancet 2004; 364:
1789–1799.
2. Kelley AS and Moravek MB. Diagnosis and management of
endometriosis. In: Shoupe D (ed.) Handbook of gynecology.
New York: Springer, 2016, pp. 1–10.
3. Brown J and Farquhar C. Endometriosis: an overview
of Cochrane Reviews. Cochrane Db Syst Rev 2014; 3:
CD009590.
4. Shah DK, Mejia RB and Lebovic DI. Effect of surgery
for endometrioma on ovarian function. J Minim Invasive
Gynecol 2014; 21(2): 203–209.
5. Taylor HS. Clinical diagnosis of endometriosis and optimal
medical therapy. Fertil Steril 2017; 108(5): 759–760.
6. Schwingshackl L, Schwedhelm C, Hoffmann G, et al. Food
groups and risk of all-cause mortality: a systematic review
and meta-analysis of prospective studies. Am J Clin Nutr
2017; 105(6): 1462–1473.
7. GBD Risk Factors Collaborators. Global, regional, and
national comparative risk assessment of 84 behavioural,
environmental and occupational, and metabolic risks or
clusters of risks, 1990–2016: a systematic analysis for the
Global Burden of Disease Study 2016. Lancet 2017; 390:
1345–1422.
Saguyod et al. 7
8. Steele CB, Thomas CC, Henley SJ, et al. Vital signs: trends
in incidence of cancers associated with overweight and obe-
sity—United States, 2005–2014. MMWR-Morbid Mortal W
2017; 66(39): 1052–1058.
9. Malik V, Willett WC and Hu FB. Global obesity: trends,
risk factors and policy implications. Nat Rev Endocrinol
2013; 9: 13–27.
10. Burghaus S, Häberle L, Schrauder MG, et al. Endometriosis
as a risk factor for ovarian or endometrial cancer—results of
a hospital-based case-control study. BMC Cancer 2015; 15:
751.
11. Ruderman R and Pavone ME. Ovarian cancer in endome-
triosis: an update on the clinical and molecular aspects.
Minerva Ginecol 2017; 69(3): 286–294.
12. Wilbur MA, Shih IM, Segars JH, et al. Cancer implications
for patients with endometriosis. Semin Reprod Med 2017;
35(1): 110–116.
13. Vercellini P, Viganò P, Somigliana E, et al. Endometriosis:
pathogenesis and treatment. Nat Rev Endocrinol 2014;
10(5): 261–275.
14. Shah DK, Correia KF, Vitonis AF, et al. Body size and
endometriosis: results from 20 years of follow-up within the
Nurses’ Health Study II prospective cohort. Hum Reprod
2013; 28(7): 1783–1792.
15. Farland LV, Missmer SA, Bijon A, et al. Associations
among body size across the life course, adult height and
endometriosis. Hum Reprod 2017; 32(8): 1732–1742.
16. Sampson JA. Metastatic or embolic endometriosis, due to
the menstrual dissemination of endometrial tissue into the
venous circulation. Am J Pathol 1927; 3(2): 93–110.
17. Nezhat C, Hajhosseini B and King LP. Laparoscopic man-
agement of bowel endometriosis: predictors of severe dis-
ease and recurrence. JSLS 2011; 15(4): 431–438.
18. Nagle CM, Bell TA, Purdie DM, et al. Relative weight at
ages 10 and 16 years and risk of endometriosis: a case-con-
trol analysis. Hum Reprod 2009; 24(6): 1501–1506.
19. Kip KE, Marroquin OC, Kelley DE, et al. Clinical impor-
tance of obesity versus the metabolic syndrome in car-
diovascular risk in women: a report from the Women’s
Ischemia Syndrome Evaluation (WISE) study. Circulation
2004; 109(6): 706–713.
20. Letsiou S, Peterse DP, Fassbender A, et al. Endometriosis
is associated with aberrant metabolite profiles in plasma.
Fertil Steril 2017; 107(3): 699–706.
21. Goetz LG, Mamillapalli R and Taylor HS. Low body
mass index in endometriosis is promoted by hepatic
metabolic gene dysregulation in mice. Biol Reprod 2016;
95(6): 115.
22. Heard ME, Melnyk SB, Simmen FA, et al. High-fat diet
promotion of endometriosis in an immunocompetent mouse
model is associated with altered peripheral and ectopic
lesion redox and inflammatory status. Endocrinology 2016;
157(7): 2870–2882.
23. Missmer SA, Chavarro JE, Malspeis S, et al. A prospective
study of dietary fat consumption and endometriosis risk.
Hum Reprod 2010; 25(6): 1528–1535.
24. Harris HR, Chavarro JE, Malspeis S, et al. Dairy-food, cal-
cium, magnesium, and vitamin D intake and endometriosis:
a prospective cohort study. Am J Epidemiol 2013; 177(5):
420–430.
25. Parazzini F, Viganò P, Candiani M, et al. Diet and endome-
triosis risk: a literature review. Reprod Biomed Online 2013;
26(4): 323–336.
26. Jamilian M and Asemi Z. The effects of soy isoflavones
on metabolic status of patients with polycystic ovary syn-
drome. J Clin Endocrinol Metab 2016; 101(9): 3386–3394.
27. Yu J, Bi X, Yu B, et al. Isoflavones: anti-Inflammatory ben-
efit and possible caveats. Nutrients 2016; 8(6): E361.
28. Danciu C, Avram S and Pavel I. Main isoflavones found
in dietary sources as natural anti-inflammatory agents. Curr
Drug Targets. Epub ahead of print 9 November 2017. DOI:
10.2174/1389450118666171109150731.
29. Tsuchiya M, Miura T, Hanaoka T, et al. Effect of soy isofla-
vones on endometriosis: interaction with estrogen receptor
2 gene polymorphism. Epidemiology 2007; 18(3): 402–408.
30. Wang D, Liu Y, Han J, et al. Puerarin suppresses invasion
and vascularization of endometriosis tissue stimulated by
17β-estradiol. PLoS ONE 2011; 6(9): e25011.
31. Cheng W, Chen L, Yang S, et al. Puerarin suppresses prolif-
eration of endometriotic stromal cells partly via the MAPK
signaling pathway induced by 17ß-estradiol-BSA. PLoS
ONE 2012; 7(9): e45529.
32. Ji M, Liu Y, Yang S, et al. Puerarin suppresses proliferation
of endometriotic stromal cells in part via differential recruit-
ment of nuclear receptor coregulators to estrogen receptor-α.
J Steroid Biochem Mol Biol 2013; 138: 421–426.
33. Yavuz E, Oktem M, Esinler I, et al. Genistein causes regres-
sion of endometriotic implants in the rat model. Fertil Steril
2007; 88(4 Suppl.): 1129–1134.
34. Chen Y, Chen C, Shi S, et al. Endometriotic implants regress
in rat models treated with puerarin by decreasing estradiol
level. Reprod Sci 2011; 18(9): 886–891.
35. Taguchi A, Wada-Hiraike O, Kawana K, et al. Resveratrol
suppresses inflammatory responses in endometrial stromal
cells derived from endometriosis: a possible role of the sir-
tuin 1 pathway. J Obstet Gynaecol Res 2014; 40(3): 770–
778.
36. Taguchi A, Koga K, Kawana K, et al. Resveratrol enhances
apoptosis in endometriotic stromal cells. Am J Reprod
Immunol 2016; 75(4): 486–492.
37. Ergenoğlu AM, Yeniel AÖ, Erbaş O, et al. Regression of
endometrial implants by resveratrol in an experimentally
induced endometriosis model in rats. Reprod Sci 2013;
20(10): 1230–1236.
38. Bruner-Tran KL, Osteen KG, Taylor HS, et al. Resveratrol
inhibits development of experimental endometriosis in vivo
and reduces endometrial stromal cell invasiveness in vitro.
Biol Reprod 2011; 84(1): 106–112.
39. Ohtsu A, Shibutani Y, Seno K, et al. Advanced glycation
end products and lipopolysaccharides stimulate interleu-
kin-6 secretion via the RAGE/TLR4-NF-κB-ROS pathways
and resveratrol attenuates these inflammatory responses in
mouse macrophages. Exp Ther Med 2017; 14(5): 4363–
4370.
40. Miyashita M, Koga K, Izumi G, et al. Effects of
1,25-Dihydroxy vitamin D3 on endometriosis. J Clin
Endocrinol Metab 2016; 101(6): 2371–2379.
41. Abbas MA, Taha MO, Disi AM, et al. Regression of endo-
metrial implants treated with vitamin D3 in a rat model of
endometriosis. Eur J Pharmacol 2013; 715(1–3): 72–75.
8 Journal of Endometriosis and Pelvic Pain Disorders 00(0)
42. Mariani M, Viganò P, Gentilini D, et al. The selective vita-
min D receptor agonist, elocalcitol, reduces endometriosis
development in a mouse model by inhibiting peritoneal
inflammation. Hum Reprod 2012; 27(7): 2010–2019.
43. Akyol A, Şimşek M, İlhan R, et al. Efficacies of vitamin
D and omega-3 polyunsaturated fatty acids on experimen-
tal endometriosis. Taiwan J Obstet Gynecol 2016; 55(6):
835–839.
44. Attaman JA, Stanic AK, Kim M, et al. The anti-inflamma-
tory impact of omega-3 polyunsaturated Fatty acids dur-
ing the establishment of endometriosis-like lesions. Am J
Reprod Immunol 2014; 72(4): 392–402.
45. Tomio K, Kawana K, Taguchi A, et al. Omega-3 polyun-
saturated fatty acids suppress the cystic lesion formation of
peritoneal endometriosis in transgenic mouse models. PLoS
ONE 2013; 8(9): e73085.
46. Xu H, Lui WT, Chu CY, et al. Anti-angiogenic effects of
green tea catechin on an experimental endometriosis mouse
model. Hum Reprod 2009; 24(3): 608–618.
47. Xu H, Becker CM, Lui WT, et al. Green tea epigallocate-
chin-3-gallate inhibits angiogenesis and suppresses vascu-
lar endothelial growth factor C/vascular endothelial growth
factor receptor 2 expression and signaling in experimental
endometriosis in vivo. Fertil Steril 2011; 96(4): 1021–1028.
48. Marziali M, Venza M and Lazzaro S. Gluten-free diet: a
new strategy for management of painful endometriosis
related symptoms? Minerva Chir 2012; 67(6): 499–504.
49. Garrote JA, Gómez-González E, Bernardo D, et al. Celiac
disease pathogenesis: the proinflammatory cytokine net-
work. J Pediatr Gastroenterol Nutr 2008; 47(Suppl. 1):
S27–S32.
50. Choung RS, Alexander JA, Katzka DA, et al. Management
of eosinophilic esophagitis and celiac disease. Curr Opin
Pharmacol 2017; 37: 118–125.
51. Stephansson O, Falconer H and Ludvigsson JF. Risk of
endometriosis in 11,000 women with celiac disease. Hum
Reprod 2011; 26(10): 2896–2901.
52. Pellicano R, Astegiano M, Bruno M, et al. Women and
celiac disease: association with unexplained infertility.
Minerva Med 2007; 98(3): 217–219.
53. Tanaka Y, Mori T, Ito F, et al. Exacerbation of endometrio-
sis due to regulatory T-cell dysfunction. J Clin Endocrinol
Metab 2017; 102(9): 3206–3217.
54. Vannuccini S, Clifton VL, Fraser IS, et al. Infertility and
reproductive disorders: impact of hormonal and inflam-
matory mechanisms on pregnancy outcome. Hum Reprod
Update 2016; 22(1): 104–115.
55. Miller JE, Ahn SH, Monsanto SP, et al. Implications of
immune dysfunction on endometriosis associated infertility.
Oncotarget 2017; 8(4): 7138–7147.
56. Glavind MT, Forman A, Arendt LH, et al. Endometriosis
and pregnancy complications: a Danish cohort study. Fertil
Steril 2017; 107(1): 160–166.
57. Alderman MH 3rd, Yoder N and Taylor HS. The systemic
effects of endometriosis. Semin Reprod Med 2017; 35(3):
263–270.
58. Logan PC, Yango P and Tran ND. Endometrial stromal
and epithelial cells exhibit unique aberrant molecular
defects in patients with endometriosis. Reprod Sci 2017;
25: 140–159.
59. Heard ME, Simmons CD, Simmen FA, et al. Krüppel-like
factor 9 deficiency in uterine endometrial cells promotes
ectopic lesion establishment associated with activated notch
and hedgehog signaling in a mouse model of endometriosis.
Endocrinology 2014; 155(4): 1532–1546.
60. Pabona JM, Simmen FA, Nikiforov MA, et al. Krüppel-like
factor 9 and progesterone receptor coregulation of decidual-
izing endometrial stromal cells: implications for the patho-
genesis of endometriosis. J Clin Endocrinol Metab 2012;
97(3): E376–E392.
61. Patel BG, Rudnicki M, Yu J, et al. Progesterone resistance
in endometriosis: origins, consequences and interventions.
Acta Obstet Gynecol Scand 2017; 96(6): 623–632.
62. Han SJ, Jung SY, Wu SP, et al. Estrogen receptor β modu-
lates apoptosis complexes and the inflammasome to drive
the pathogenesis of endometriosis. Cell 2015; 163(4):
960–974.
63. Xu J, Chi F, Guo T, et al. NOTCH reprograms mitochon-
drial metabolism for proinflammatory macrophage activa-
tion. J Clin Invest 2015; 125(4): 1579–1590.
64. Hsu EC, Kulp SK, Huang HL, et al. Function of integrin-
linked kinase in modulating the stemness of IL-6-abundant
breast cancer cells by regulating γ-secretase-mediated
notch1 activation in caveolae. Neoplasia 2015; 17(6): 497–
508.
65. Su RW, Strug MR, Jeong JW, et al. Aberrant activation of
canonical Notch1 signaling in the mouse uterus decreases
progesterone receptor by hypermethylation and leads to
infertility. Proc Natl Acad Sci U S A 2016; 113(8): 2300–
2305.
66. Grandi G, Mueller M, Bersinger N, et al. Progestin sup-
pressed inflammation and cell viability of tumor necro-
sis factor-α-stimulated endometriotic stromal cells. Am J
Reprod Immunol 2016; 76(4): 292–298.
67. Burns KA, Thomas SY, Hamilton KJ, et al. Early endome-
triosis in females is directed by immune-mediated estrogen
receptor α and IL-6 cross-talk. Endocrinology 2017; 159:
103–118.
68. Grandi G, Mueller MD, Papadia A, et al. Inflammation
influences steroid hormone receptors targeted by progestins
in endometrial stromal cells from women with endometrio-
sis. J Reprod Immunol 2016; 117: 30–38.
69. Almassinokiani F, Khodaverdi S, Solaymani-Dodaran M,
et al. Effects of vitamin D on endometriosis-related pain: a
double-blind clinical trial. Med Sci Monit 2016; 22: 4960–
4966.
70. Ciavattini A, Serri M, Delli Carpini G, et al. Ovarian endo-
metriosis and vitamin D serum levels. Gynecol Endocrinol
2017; 33(2): 164–167.
71. Hopeman MM, Riley JK, Frolova AI, et al. Serum polyun-
saturated fatty acids and endometriosis. Reprod Sci 2015;
22(9): 1083–1087.